Hypoplastic left heart syndrome (HLHS) is a severe and devastating heart defect that affects ~ 1 in 5-10,000 children born each year and accounts for 25% of all neonatal deaths from congenital heart disease. The significant impact of HLHS stems from a compromise of left- sided cardiac structures (mitral and aortic valves and the left ventricle or LV). Etiologic mechanisms leading to HLHS are unknown making advances in prevention challenging. Genetic studies show that HLHS does not follow simple Mendelian genetics but exhibits complex inheritance with contributions from both genetic and environmental factors. Our long- term goal is to help eradicate HLHS through better understanding of the mechanism(s) involved in its pathogenesis. We propose a novel hypothesis for the pathogenesis of HLHS. Our hypothesis is that HLHS is an expression of a form of rheumatic heart disease (RHD) in the fetus. RHD is a serious sequelae of pharyngeal ss-hemolytic group A streptococcal (strep) infection, most commonly manifest in the form of strep throat. In RHD anti-strep antibodies are generated in response to the strep infection cross-react with human valvular and myocardial antigens, through a mechanism known as molecular mimicry. This initiates an inflammatory and immunologic cascade that ultimately damages the aortic/mitral valves and the adjacent LV. We propose a similar mechanism for the pathogenesis of HLHS in which maternal antibodies produced in response to antecedent (and recurrent) strep infection, cross the placenta and damage the fetal heart in the susceptible host. The injury to the fetal valves and LV causes alterations in flow that then leads to LV hypoplasia. Lack of animal models of HLHS has hindered research that could translate to humans. The goal of this proposal is to develop a animal model of HLHS. In a novel rat model we will show that transplacental passage of antibodies produced in response to prior immunization with strep antigens can lead to offspring with HLHS-like pathology. Preliminary studies in a small number of animals have confirmed the feasibility of our proposal. Development of an animal model that clinically recapitulates this disease is essential to furthering the efforts to improve understanding of HLHS and define its mechanisms of pathogenesis as well as potentially identify therapeutic targets. A good animal model for HLHS will have a sustained impact on this field of research.